DESCRIPTION A subject-matter of the present invention is novel technetium or rhenium complexes which can be used in radiopharmaceutical products for diagnosis or therapy and which exhibit the advantage of being able to comprise a biological vector.

It relates more particularly to technetium or rhenium complexes in which the metal is in the III oxidation state in the form of an M3+ ion.

Radiopharmaceutical products comprising these complexes are advantageous, in particular when they comprise a biological vector which renders them suitable for the diagnosis or for the therapy of various pathologies.

State of the prior art Radiopharmaceuticals form a class of radioactive compounds generally composed of a-or-emitting radioelement. These molecules may be used alone, when they exhibit an intrinsic activity for the biological target, or else can be combined with an active biological molecule, conferring the desired tropism on the combination. Thus, the key point of this discipline is based on the development of novel radiopharmaceuticals specific for an organ, for a physiological function or for a pathology. For this, the isotope must first of all emit y photons or P particles detectable by existing scintigraphic equipment. Among the radioelements most widely used in

scintigraphy, technetium-99m emerges as being the radioisotope of choice for nuclear medicine.

For some years, efforts have also been directed at the search for novel radiopharmaceuticals with a therapeutic purpose. The radiotracers used in therapy are radiolabelled molecules designed to deliver, in the most specific way possible, therapeutic doses of ionizing rays to sites in the body exhibiting physiological disorders (cancerous tumours). This technique, referred to as"metabolic radiotherapy", comes under nuclear medicine. In this context, rhenium and in particular the Re and 188Re isotopes prove to be highly promising radioelements.

Radiopharmaceutical products based on technetium or on rhenium are already known.

Thus, nitridobis (dithiocarbamato) Tc-99m complexes, in which the technetium is in the V oxidation state, have been provided in FR-A-2 698 272 [1] as products for the in vitro labelling of blood cells and in particular of leukocytes for the purpose of the anatomical locating of inflammatory or infectious foci. These complexes correspond to the formula: (Tc=N) I/L in which L1 and L2 represent two ligands of formula: R1 necessarily being an ethoxy group in at least one of the ligands Ll and L2, whereas it can be an ethyl group

or an ethoxy group in the other of these ligands.

More recently, a rhenium complex with rhenium in the III oxidation state, and therefore a complex which is more stable chemically and thermodynamically than the preceding complexes, has been provided by F. Mevellec et al. in Inorg. Chem. Comm., 2,1999, 230-233 [2], also for the in vitro labelling of leukocytes. This complex corresponds to the formula: [Re (S3CPh) 2 (S2CPh)] and thus comprises three ligands, including two trithioperoxybenzoates and one dithiobenzoate.

The complexes disclosed in the document [1] and the document [2] exhibit a selective affinity with respect to leukocytes. Thus, placed in the presence of a blood sample, they are capable of selectively binding to the leukocytes present in this sample, this selectivity being expressed more particularly with respect to granulocytes, in the case of the complexes of the document [1], and lymphocytes, in the case of the complex of the document [2].

On the other hand, they do not comprise a biological molecule capable of acting as vector for them within à living organism and of directing them to a target other than an inflammatory or infectious focus.

Complexes based on rhenium sulphides have also been disclosed by Wei et al. in J. Am. Chem. Soc., 1990, 112,6433-6434 [3], and by McConnachie and Stiefel in Inorg. Chem. , 1997,36, 6144-6145 [4] and Inorg. Chem. , 1999,38, 964-972 [5], but for use in the field of

catalysis.

The Inventors therefore set themselves the target of providing technetium and rhenium complexes which, while exhibiting excellent chemical and thermodynamic stability, can comprise a biological vector capable of conferring on them a specificity with regard to specific cells, a specific-physiological function or a specific pathology.

Description of the invention A specific subject-matter of the present invention is novel technetium or rhenium complexes in which the technetium or rhenium is in the III oxidation state and which can additionally comprise a biological vector suitable for the diagnosis or therapeutic treatment to be carried out.

According to the invention, these technetium or rhenium complexes correspond to the formula (I): [M (R1CS3) 2L] (I) in which M is Tc or Re, R1 represents an alkyl, cycloalkyl, aralkyl or aryl group which is unsubstituted or substituted by one or more substituents chosen from halogen atoms, the hydroxyl group, alkyl groups and alkoxy groups, and L is a dithiolate ligand, with the exception of the ligand of formula R2CS2 in which R2 is identical to R1.

The complexes according to the invention thus exhibit the distinguishing feature of comprising both a radioelement in the III oxidation state, which confers

on them a highly satisfactory chemical and thermodynamic stability, and a dithiolate ligand L which comprises a group R2 different from the group of the other two ligands.

It is thus possible, in the case where it is desired to couple these complexes to a biological vector, to attach this vector to this dithiolate ligand alone and not to all the ligands and, consequently, to prevent steric hindrance which would have the effect of preventing the vector from binding to its target.

In accordance with the invention, the dithiolate ligand can be chosen from the dithiocarbamate, xanthate, dithiophosphate, dithiophosphonate, dithiophosphinate, dithiocarboxylate, 1,2-dithiolate and 1,2-dithiolene ligands.

The ligand L is preferably a dithiocarbamate of formula (II) : 3 NCS2 (II) R4 in which R3 and R4, which can be identical or different, represent a hydrogen atom, a Ci to Ciao, preferably C1 to C5, alkyl group, a C6 to C1O aryl group or a C7 to C12 aralkyl group, the alkyl, aryl or aralkyl groups optionally comprising one or more groups chosen from OH, SH, COOH, COOR, NH2 NHR, NR2, CONH2, CONHR, CONR2, NCSR and SCNR where the R groups, which can be identical or different, represent an alkyl or aryl group, groups capable of reacting with a biological molecule and groups derived from a biological molecule which are optionally connected to the alkyl, aryl or

aralkyl group via a spacer, or in which R3 and R4 form, together with the nitrogen atom to which they are bonded, a heterocycle having from 3 to 5 carbon atoms optionally comprising another heteroatom chosen from 0, S and N, this heterocycle being unsubstituted or substituted by one or more Ci to C10 alkyl, C6 to Coo aryl or C7 to C12 aralkyl groups, the alkyl, aryl or aralkyl groups optionally comprising one or more groups chosen from OH, SH, COOH, COOR, NH2, NHR, NR2, CONH2, CONHR, CONR2, NSCR and SCNR where the R groups, which can be identical or different, represent an alkyl or aryl group, groups capable of reacting with a biological molecule and groups derived from a biological molecule which are optionally connected to the alkyl, aryl or aralkyl group via a spacer.

The presence of such a ligand is particularly advantageous as it can comprise either a group capable of reacting with a biological molecule, such as a hydroxyl, thiol, carboxylic acid, ester, amine, amide, thiocyanate or isothiocyanate group, or a group derived from a biological molecule which is optionally connected to the alkyl, aryl or aralkyl group of the ligand via a spacer.

This spacer can correspond to one of the following formulae: (CH2) n S (CH20) n s (CH2S) n and (CH2NR) n in which R is as defined above and n is an integer ranging from 1 to 5.

The biological molecules capable of being attached to this ligand can be highly varied in nature. They can

be, for example, antibodies, proteins, peptides, members of a ligands/receptors group, hormones or nucleic acids. Mention may be made, by way of examples, of molecules derived from somatostatin, such as octreotide, labels, ligands of the serotonin receptors, such as 1- (2-methoxyphenyl) piperazine, biotin, and the like.

In the case where the complexes comprise 1-(2-methoxyphenyl) piperazine, which has a high affinity for some cerebral receptors, the radiopharmaceutical products comprising such a complex will attach preferentially to the receptors specific for this biological molecule. The concentration of receptors of this type in the various cerebral regions can thus be measured experimentally. These radiopharmaceutical products can also be used for monitoring the inhibition of these receptors by other unlabelled molecules, for example medicaments or drugs, by measuring the variation in the concentration of receptors of this type due to the unlabelled molecule.

Depending on the biological vector used, the complexes according to the invention can be used as radiopharmaceuticals for detecting or treating cancers, neurodegenerative diseases (Parkinson's disease, Alzheimer's disease or multiple sclerosis) or dysfunctions of the cardiovascular system.

In accordance with the invention, the group R1 of the sulphur-comprising ligands R1CS3 and the ligand L are chosen so that the latter is a more electronegative molecule than the said sulphur-comprising ligands, this being because the Inventors have found that this arrangement results in particularly stable complexes

being obtained.

The group R1 of the sulphur-comprising ligands R1CS3 can be an aliphatic, alkyl, cycloalkyl, aralkyl or aryl group. This group can be unsubstituted or substituted by one or more substituents chosen from halogen atoms, for example fluorine, the hydroxyl group, alkyl groups and alkoxy groups.

The alkyl groups used for R1 can be linear or branched C1 to C12 groups, preferably groups having 3 to 13 carbon atoms.

The cycloalkyl groups used for R1 preferably have 3 to 7 carbon atoms, for example 6 carbon atoms.

The aryl groups used for or can be of the phenyl or naphthyl type.

The aralkyl groups used for or can be of the C6H5 (CH2) n type with n ranging from 1 to 3; preferably, n is equal to 1 or 2.

Preferably, according to the invention, the group R1 is an optionally substituted aryl, aralkyl or cyclohexyl group.

Advantageously, when R1 is an aryl group, it is chosen from the phenyl group, the phenyl group substituted by one or more methyl, ethyl, propyl, butyl, ethoxy, methoxy and/or hydroxyl groups and/or by one or more fluorine, chlorine, bromine and/or iodine atoms, the naphthyl group and the naphthyl group substituted by a group chosen from alkyl or alkoxy groups and halogen atoms.

In the case where R1 is an aralkyl group, the latter is advantageously the benzyl or phenethyl group.

In the ligand L of dithiocarbamate type, R3 and R4 are chosen according to the use envisaged for the complex produced.

Mention may be made, as example of dithiocarbamate ligands used in the invention, of the ligands in which R3 and R4 have the meanings given below: 1) R3 and R4 are identical and represent a methyl, ethyl or ethoxy group; 2) R3 is the ethyl group and R4 is the hydroxyethyl group; 3) R3 and R4 form, with the nitrogen atom to which they are bonded, a piperidine, pyrrolidine, pyridine, piperazine, ethylpiperazine or morpholine ring; 4) R3 is a hydrogen atom and R4 represents the group of formula (III) : in which n is an integer ranging from 1 to 6, preferably equal to 2; and 5) R3 and R4 form, together with the nitrogen atom to which they are bonded, the group of formula (X):

in which n is an integer ranging from to 6, preferably equal to 2.

The technetium and rhenium complexes described above can be used in radiopharmaceutical products.

Consequently, another subject-matter of the invention is a radiopharmaceutical product comprising a technetium or rhenium complex as described above in which M is Tc, Re or Re.

Another subject-matter of the invention is a process for the preparation of the technetium or rhenium complexes corresponding to formula (I).

According to a first embodiment of this process, the technetium or rhenium complex of formula (I) is obtained by carrying out the following stages: - reacting a salt of formula (IVa) or (IVb): (MO4) -Za+ (IVa) [MOC14]-Za+ (IVb) in which M is as defined above and Za+ is a pharmaceutically acceptable cation, with a reducing agent, and

- adding, to the reaction mixture, a dithiocarboxylate of formula (V): (R1CS2) (V) in which R1 is as defined above and Zb+ represents a pharmaceutically acceptable cation, and a salt L-X+ where L is as defined above and X+ is a cation chosen from sodium and potassium.

According to a second embodiment of the process of the invention, the complexes of formula (I) are obtained from a technetium or rhenium complex of formula (VI): [M (R1CS3) 2 (RlCS2)] (VI) in which M and R1 are as defined above, by bringing this complex into contact with a salt L-X+, where L is as defined above and X+ is a cation chosen from sodium and potassium, in order to exchange the ligand R1CS2 with the ligand L.

The complexes of formula (VI) used as starting materials in this second embodiment of the process of the invention can be prepared by a process comprising the following stages: - reacting a salt of formula (IVa): (M04)-Za+ (IVa) in which M is as defined above and Za+ is a pharmaceutically acceptable cation, with a reducing agent, and - adding, to the reaction mixture, a dithiocarboxylate of formula (V):

(RCS2)'Zb" (V) in which R1 is as defined above and Zb+ represents a pharmaceutically acceptable cation.

In these various methods of preparation, the pharmaceutically acceptable cations used for Za+ can be alkali metal or alkaline earth metal ions, for example sodium, ammonium ions and quaternary ammonium ions, such as NH4 and NBu4, with Bu representing the butyl group.

The pharmaceutically acceptable cations used for Zb+ can be chosen from MgX+, where X is a halogen atom, such as Br or Cl, quaternary ammonium cations and alkali metal ions, such as sodium.

The quaternary ammonium cations can be, for example, of the NR4 type, where R is an alkyl group, for example methyl. Use may also be made of quaternary ammonium cations of the piperidinium type of formula C. 5H, ONH2+- In both embodiments of the process of the invention, the reducing agent used can be of various types. Use may in particular be made of a reducing agent composed of a tin salt in combination with a complexing agent having a higher complexing power for the tin than that of the dithiocarboxylate.

This complexing agent can be of the phosphonate, polyphosphate and polyaminocarboxylic acid type.

Mention may be made, as examples of such complexing agents, of ammonium or alkali metal or alkaline earth metal pyrophosphates, ammonium or alkali metal or

alkaline earth metal glucoheptonates, ammonium or alkali metal diethylenetriaminepentaacetates, ammonium or alkali metal or alkaline earth metal ethylenediaminetetraacetates, ammonium or alkali metal or alkaline earth metal 1,2-diaminopropane- N, N, N', N'-tetraacetates, ammonium or alkali metal or alkaline earth metal gluconates, ammonium or alkali metal or alkaline earth metal methylenediphosphonates, ammonium or alkali metal or alkaline earth metal hydroxymethylenediphosphonates, and ammonium or alkali metal or alkaline earth metal citrates.

Use may be made in the invention, by way of example, of a tin salt composed of tin chloride in combination with a complexing agent chosen from calcium gluconate, 1, 2-diaminopropane-N, N, N', N'-tetraacetic acid and a dithiocarbazate DTCZ.

Use may also be made, according to the invention, of reducing agents composed of a phosphine or of one of its derivatives in combination with hydrochloric acid.

Mention may be made, as example of phosphine and of phosphine derivative, of triphenylphosphine and sodium triphenylphosphine-tri-meta-sulphonate P (C6H4SO3) 3Na3.

In the process of the invention, the metal M, which was initially in the'VII oxidation state, is reduced to the III oxidation state, while a portion of the dithiocarboxylate ligand is oxidized to trithioperoxycarboxylate.

The amounts of reducing agent used in this process are chosen according to the amount of pertechnetate or perrhenate initially introduced.

In the case of the pertechnetate Tc99m, for activities of 30 MBq to 4 GBq, use may be made of amounts of reducing agent ranging from 0.01 to 1 mg in the case of SnCl2-2H20, in the presence of an excess of complexing agent with respect to the tin chloride.

When a triphenylphosphine. is used as reducing agent, the amounts used are of the order of 0.1 to 5 mg, in the case of pure triphenylphosphine, and of 0.2 to 10 mg, in the case of sodium triphenylphosphine-tri- meta-sulphonate. An aqueous HC1 solution is added with these reducing agents in order to obtain 1 x 10-2 to 1 x 10-i mol/1 of HC1 in the reaction medium.

Despite the similarity in the chemical properties between the pertechnetate and the perrhenate, it is known that, for the reduction reaction, the latter ion requires larger amounts of reducing agent than those employed for the pertechnetate ion.

Furthermore, in the case where the radioactive metal is rhenium-186, an isotope having a low specific activity, the amount of perrhenate used is greater in order to obtain the same activity; consequently, to reduce this species, larger amounts of reducing agent will be used than in the case of the rhenium-188 isotope.

Thus, use may be made of 0.1 to 5 mg of reducing agent in the case of SnC12-2H2O, 0.1 to 10 mg in the case of pure triphenylphosphine and 0.2 to 20 mg in the case of sodium triphenylphosphine-tri-meta-sulphonate.

A sufficient amount of dithiocarboxylate and optionally of L-X+ salt, preferably dissolved in physiological

saline, is subsequently added to the reaction medium.

The reaction of the ligand (s) with the pertechnetate or perrhenate is carried out under hot conditions, for example at a temperature of 100°C.

In the first embodiment of the process of the invention, the operation is carried out in an organic solvent, such as dichloromethane, or in water by adding, to the solution of the salts of the ligand L and of R1CS2, a solution of the salt of formula (MO4)-Z in the same solvent.

In the second embodiment of the process of the invention, an exchange reaction is carried out between the technetium or rhenium complex of formula (VI) and a salt of the ligand L. For this exchange reaction, a salt of the ligand L in solution in an organic solvent, such as methanol, or in water is added to the complex of formula (VI) in solution in an organic solvent, such as dichloromethane, or in suspension in water.

According to the invention, when the ligand L comprises a group capable of reacting with a biological molecule, the process can comprise an additional stage consisting in reacting the complex formed above with a biological molecule in order to attach it to the ligand L via this group. The biological molecule can also be introduced onto the ligand L beforehand, in order to directly obtain a complex comprising this biological molecule.

A further subject-matter of the invention is a kit for the preparation of a radiopharmaceutical product comprising a complex of formula (I) : [M (R1CS3) 2L] (I)

in which M is 99mTc, 186Re or 183Re, R1 represents an alkyl, cycloalkyl, aralkyl or aryl group which is unsubstituted or substituted by one or more substituents chosen from halogen atoms, the hydroxyl group, alkyl groups and alkoxy groups, and L is a dithiolate ligand, with the exception of the ligand of formula R2CS2 in which R2 is identical to Ru, characterized in that it comprises: - a first bottle comprising a tin salt in combination with a complexing agent, or a phosphine and hydrochloric acid, - a second bottle comprising a dithiocarboxylate of formula (R1CS2)-Zb+ in which R3-is as defined above and Zb+ represents a pharmaceutically acceptable cation, and - a third bottle comprising a salt L-X+ where L is as defined above and X+ is a cation chosen from sodium and potassium.

When the kit is intended to implement the first embodiment of the process of the invention, the first and the second bottles can be replaced by a single bottle and, in this case, the kit comprises: - a first bottle comprising a tin salt in combination with a complexing agent, or a phosphine and hydrochloric acid, and - a second bottle comprising a dithiocarboxylate of formula (R1CS2)-Zb+ in which R1 is as defined above and Zb+ represents a pharmaceutically acceptable cation, and a salt L-X+ where L is as defined above and X+ is a cation chosen from sodium and potassium.

Generally, in both embodiments of the kit, the first bottle comprises tin chloride SnC12-2H20 in combination

with a complexing agent chosen from calcium gluconate, 1, 2-diaminopropane-N, N, N', N'-tetraacetic acid and a dithiocarbazate DTCZ. According to an alternative implementation, this first bottle comprises triphenylphosphine or sodium triphenylphosphine-tri- meta-sulphonate, and hydrochloric acid.

In both embodiments of the kit, the latter can additionally comprise a bottle comprising a biological molecule.

The radiopharmaceutical products comprising the complexes of the invention are particularly advantageous as they can be adapted to various pathologies, depending on the nature of the ligand L and of the biological molecule with which it is combined.

Thus, it is possible to obtain, in accordance with the invention, radiopharmaceutical products labelled with a suitable biological vector.

Furthermore, such radiopharmaceutical products with technetium 99mTc or with rhenium : L 8 6Re or 188Re can be prepared in less than one hour from a kit comprising three bottles respectively comprising the reducing agent (tin salt-gluconate), the dithiocarboxylate (R1CS2)-Zb+ and the salt of the ligand L, for example a dithiocarbamate.

Other characteristics and advantages of the invention will become more clearly apparent on reading the following examples, given, of course, by way of illustration and without implied limitation.

Detailed description of the embodiments The following Examples 1 to 11 illustrate the preparation of rhenium and technetium complexes in accordance with the invention.

Examples 1 to 6 illustrate the first embodiment of the process of the invention. Examples 7 to 11 illustrate the second embodiment of the process of the invention.

Examples 12 to 14 illustrate the preparation of dithiocarbamate ligands of use in the preparation of the complexes of the invention.

Example 1: Preparation of bis (trithioperoxybenzoato)- (diethyldithiocarbamato) rhenium (III) [Re (PhCS3) 2 (Et2NCS2)] A mixture of 0.407 g (1.7 mmol) of piperidinium phenyldithiocarboxylate salt and 0.383 g (1.7 mmol) of sodium diethyldithiocarbamate in the minimum amount of dichloromethane (20 ml) is added dropwise to a solution comprising 0.100 g (0.170 mmol) of [ReOCl4] [NBu4] in dichloromethane (5 ml). After stirring for 6 hours at ambient temperature, the solvent is evaporated and the residue, taken up in dichloromethane, is chromatographed on a column of silica gel (eluent: petroleum ether/dichloromethane: 70/30) and then recrystallized from a petroleum ether/dichloromethane mixture.

0. 090 g of complex is thus obtained in the form of khaki green crystals (yield of 75%).

The characteristics of this complex are as follows:

- M = 705.11 ; - melting point M. p. = 164-166°C ; - Rf = 0.50 (petroleum ether/CH2Cl2 : 70/30) ; 1H NMR (CDC13) : 1. 19 (t, J = 7.1 Hz, 6H, CH3), 3.60 (m, 4H, CH2), 7. 31 (t, J = 8.1 Hz, 2H, H8), 7.53 (t, J = 8.1 Hz, 4H, H7), 8. 07 (d, J = 8.6 Hz, 4H, H6).

13C NMR (CDC13) : 12.8 (CH3), 44.4 (CH2), 128.1 and 132.4 (C6 and C7), 132.8 (C8), 134.9 (C5), 204.5 (NCS2), 233.4 (CS3).

Mass spectrometry (FAB) : m/z = 704. 7: [M+] 551.8 : [H+#- (PhCS2)].

Elemental analysis: empirical formula: CI9H2oNS8Re Experimental: % C = 32.44 % H = 2.87 % S = 36.41 Calculated : % C = 32.35 % H = 2. 86 % S = 36.36 Infrared (KBr disc): 2 963 (w), 2 921 (w), 2 852 (w), 1 504 (s), 1 482 (m), 1 454 (m), 1 440 (s), 1 377 (w), 1 354 (w), 1 300 (w), 1 275 (m), 1 241 (m), 1 208 (m), 1 179 (w), 1 149 (m), 1 078 (w), 1 028 (w), 1 001 (s), 990 (s, vC=S), 908 (m), 755 (s), 687 (s), 544 (s, 454 (m), 399 (m, vRe s)- Example 2: Preparation of bis (trithioperoxybenzoato)- (dimethyldithiocarbamato) rhenium (III) [Re (PhCS3) 2 (Me2NCS2)] The same procedure as in Example 1 is followed in preparing this complex, using sodium dimethyldithiocarbamate instead of sodium diethyldithiocarbamate. 0.080 g of green crystals of the complex (yield = 69%) is thus obtained. The characteristics of the complex are as follows: - M = 677.05 ;

-M. p. = 160-162°C ; - Rf = 0.45 (petroleum ether/CH2Cl2 : 70/30) ; H NMR (CDC13) : 3.24 (s, 6H, CH3), 7.31 (t, J = 7. 6 Hz, 2H, Har), 7.52 (t, J = 8. 1 Hz, 4H, Har), 8.07 (dd, J = 8.1 Hz and J = 2.5 Hz, 4H, Har).

13 C NMR (CDC13) : 39. 5 (CH3), 128. 1 and 132. 4 (CHo and m) t 132.9 (CHp), 134.9 (Cq), 207.1 (NCS2), 233.8 (CS3).

Elemental analysis: empirical formula: Cl7Hi6NS$Re Experimental: % C = 30.21 % H = 2.40 % S = 37.85 Calculated: % C = 30.16 % H = 2.38 % S = 37.89 Infrared (KBr disc): 1 594 (w), 1 569 (w), 1 533 (w), 1 481 (m), 1 441 (m), 1 393 (s), 1 329 (w), 1 261 (m), 1 252 (m), 1 148 (m), 1 098 (w), 1 027 (w), 1 009 (m), 990 (s, vC=S), 775 (s), 681 (s), 544 (s, vS-S), 454 (m), 399 (m, vRe-S).

Example 3: Preparation of bis (trithioperoxybenzoato)- (N-piperidyldithiocarbamato) rhenium (III) [Re (PhCS3) 2 (C5H10NCS2)] The same procedure as in Example 1 is followed in preparing this rhenium complex, using piperidinium piperidyldithiocarbamate instead of sodium diethyldithiocarbamate.

The piperidyldithiocarbamate is obtained in the following way.

4.25 g (0. 050 mol, 5 ml) of piperidine are dissolved in 100 ml of ether in a two-necked flask and 2.40 g (0.060 mol) of NaOH are added to the solution with stirring. The mixture obtained is cooled to-15°C using

a bath of liquid nitrogen and 3.95 g (0.052 mol, 3.2 ml) of carbon disulphide are added dropwise to the solution. The mixture is maintained at-15°C for 30 minutes. After returning to ambient temperature with stirring, the solid obtained is filtered off, washed with ether and dried under vacuum, and then recrystallized from an isopropanol/ether (1: 2) mixture.

5.03 g of white crystals, comprising 41% of piperidinium piperidyldithiocarbamate and a very small amount of sodium piperidyldithiocarbamate, are thus obtained.

The characteristics of the piperidinium salt are as follows: H NMR: 1.55 (m, 8H, 2H3, 4H5 and 2H6), 1.69 (m, 4H, 4H2), 3.07 (t, 4H, H4, J45 = 5. 6 Hz), 4.17 (t, 4H, Hl, Jl-2 = 5.3 Hz).

3C NMR : 21.1 (C6), 21.9 (C3), 23.3 (C5), 25.2 (C2), 44. 2 (C4), 52. 6 (C1), 202.2 (C-S).

Infrared spectrum (v in cm-1) : 2 930 (s, CH2), 2 852 (m, CH2), 1 449 (w, CH2), 1 409 (s, C-N), 1 218 (s, C=S) By following the procedure of Example 1 and by using this dithiocarbamate, 0.085 g of complex in the form of green crystals (yield = 70%) is obtained.

The characteristics of the complex are as follows: - M = 716.96 ; -M. p. = 196-198°C ; - Rf = 0.46 (petroleum ether/CH2C12 : 70/30) ;

1H NMR (CDC13) : 1. 60 (s, br, 4H, CH2), 1. 65 (s, br, 2H, CH2), 3.74 (s, br, 4H, NCH2), 7.31 (t, J = 7.6 Hz, 2H, Har), 7.54 (t, J = 7. 6 Hz, 4H, Har), 8.07 (d, J = 8. 1 Hz, 4H, Har).

13C NMR (CDC13) : 23.8 (CH2), 25.3 (CH2), 47.6 (CH2) 128.1 and 132.4 (CHar), 132.9 (CHar), 134.9 (Car), 203.5 (NCS2), 233. 5 (CS3).

Mass spectrometry (FAB): m/z = 716.891914 : [M+#] ; 563.9 : [M+#- (PhCS2)] ; 531.9 : [Re- (PhCS3)].

Elemental analysis: empirical formula: C2oH2oNS8Re Experimental: % C = 33.29 % H = 2.79 % S = 35.81 Calculated: % C = 33.50 % H = 2.81 % S = 35.77 Infrared (KBr disc): 2 963 (w), 2 921 (w), 2 852 (w), 1 498 (s), 1 441 (s), 1 261 (s), 1 243 (m), 1 096 (s), 1 023 (s), 800 (s, vc=s), 755 (m), 678 (m), 544 (s, vs-s), 454 (m), 399 (m, uRe-S).

Example 4: Preparation of bis (trithioperoxybenzoato)- (N-morpholinodithiocarbamato) rhenium (III) [Re (PhCS3) 2 (O (CH2CH2) 2NCS2)] The same procedure as in Example 1 is followed, using sodium morpholinodithiocarbamate instead of sodium diethyldithiocarbamate.

0.069 g of complex is thus obtained in the form of green crystals (yield = 55%).

The characteristics of the complex are as follows: - M = 719. 04 ; - M. p. >260°C ; - Rf = 0.16 (petroleum ether/CH2Cl2 : 70/30);

1H NMR (CDC13): 3.63 (t, J = 4.1 Hz, 4H, NCH2), 3.77 (t, J = 4.0 Hz, 4H, OCH2), 7. 48 (m, 6H, Har), 8. 02 (dd, J = 1.0 and 8.4 Hz, 4H, Har).

13C NMR (CDCl3) : 46. 1 (NCH2), 65. 9 (OCH2), 128. 1, 132. 5 and 133. 0 (CHar), 134. 9 (Car), 205. 8 (NCS2), 248. 6 (CS3).

Elemental analysis: empirical formula: C19Hl8NOReSe.

Experimental: % C = 32.02 % H = 2. 55 % S = 35.81 Calculated: % C = 31.70 % H = 2.50 % S = 35.70 Infrared (KBr disc): 1 492 (s), 1 442 (m), 1 428 (m), 1 298 (w), 1 268 (w), 1 235 (s), 1 183 (w), 1 114 (w), 1 028 (w), 1 008 (s, vC-S), 994 (m, vC-s), 908 (w), 882 (w), 757 (m), 680 (w), 551 (w), 544 (s, Vs-s),. 454 (m), 399 (m, vRe-S).

Example 5: Preparation of bis (trithioperoxybenzoato)- (N-ethyl-N- (2-hydroxyethyl) dithiocarbamato) rhenium (III) [Re (PhCS3) 2 ( (HOCH2CH2) N (Et) CS2)] The same procedure as in Example 1 is followed, except that sodium N-ethyl-N- (2-hydroxyethyl) dithiocarbamate is used instead of sodium diethyldithiocarbamate.

0.063 g of complex is thus obtained in the form of green crystals (yield = 50%).

The characteristics of this complex are as follows: - M = 721.06 ; -M. p. = 196-198°C ; - Rf = 0.46 (petroleum ether/CH2Cl2 : 70/30); 1H NMR (CDC13) : 0.81 (t, J = 7.1 Hz, 3H, CH3), 1. 60 (s, br, 2H, NCH2CH3), 1. 65 (s, br, 2H, CH2CH2N), 3. 67 (q, J = 7.0 Hz, 2H, OCH2CH2N), 7. 26 (t, J = 7. 6 Hz, 2H,

Har), 7. 47 (t, J = 7. 6 Hz, 4H, Har), 8. 01 (d, J = 8. 1 Hz, 4H, Har).

13c NMR (CDC13) : 23.8 (CH3), 24.6 (NCH2), 25.3 (NCH2), 47. 6 (OCH2), 128. 1 and 132. 4 (CHar), 132. 9 (CHar), 134.9 (Car), 203. 5 (NCS2), 233. 5 (CS3).

Elemental analysis: empirical formula: ClgH20NOReS$.

Experimental: % C = 31.51 % H = 2.79 % S = 35.77 Calculated: % C = 31.60 % H = 2.80 % S = 35.60 Infrared (KBr disc): 2 963 (w), 2 921 (w), 2 852 (w), 1 499 (s), 1 482 (m), 1 442 (s), 1 261 (w), 1 245 (s), 1 180 (w), 1 118 (w), 1 029 (w), 1 004 (s, vC=S), 992 (s, vC-S), 757 (s), 580 (m), 544 (s, vS-S), 454 (m), 399 , vRe-S).

Example 6 : Preparation of bis (trithioperoxy- naphthoato) (diethyldithiocarbamato) rhenium (III) [Re (CloH7CS3) 2 (Et2NCS2)] The same procedure as in Example 1 is followed, except that piperidinium dithionaphthoate is used instead of the piperidinium phenyldithiocarboxylate salt.

0.70 g of the complex is thus obtained in the form of green crystals (yield = 50%).

The characteristics of this complex are as follows: - M = 805.18 ; -M. p. = 218°C ; - Rf = 0.53 (petroleum ether/CH2Cl2 : 70/30) ; H NMR (CDC13) : 1. 20 (t, J = 7.1 Hz, 6H, CH3), 3. 80 (q, J = 7.1 Hz, 4H, NC_2), 7. 85 (dd, J = 1.5 Hz and J = 6.9 Hz, 2H, Har), 7. 90 (t, J = 6.6 Hz and J = 7. 9 Hz, 2H,

Har), 7. 98 (t, J = 7.4 Hz and J = 7.9 Hz, 2H, Har), 8. 07 (d, J = 6.9 Hz, 2H, Har), 8. 20 (d, J = 8.1 Hz, 2H, Har), 8.25 (d, J = 7.6 Hz, 2H, Har), 8.44 (d, J = 8.1 Hz, 2H, Har)- 3C NMR (CDC13) : 12.8 (CH3), 44.6 (CH2), 125.8, 126.4, 127.3, 128.5, 130.4, 130.5, 131.2, 132.9, 133.5 and 133.5 (10 Car), 207.1 (CS2), 233.6 (CS3).

Elemental analysis: empirical formula: C27H24NReS8.

Experimental: % C = 40.44 % H = 3. 02 %S = 31.96 Calculated: % C = 40.30 % H = 3.00 % S = 31.90 Infrared (KBr disc): 1 505 (s), 1 456 (w), 1 436 (m), 1 390 (w), 1 352 (w), 1 276 (m), 1 240 (m), 1 208 (w), 1 152 (w), 1 076 (w), 1 002 (s, vC=S), 856 (w), 796 (s), 770 (s), 453 (w), 428 (w), 544 (s, vS-S), 454 (m), 399 , vRe-s)- Example 7: Preparation of bis (trithioperoxybenzoato)- (diethyldithiocarbamato) rhenium (III) [Re (PhCS3) 2 (Et2NCS2)] In this example, the complex of Example 1 is prepared by following the second embodiment of the process of the invention. a) Preparation of the complex [Re (S3CPh) 2 (S2CPh) ] 0.300 g (1.25 mmol) of piperidinium phenyldithiocarboxylate salt, dissolved in the minimum amount of dichloromethane (30 ml), is added dropwise to a solution comprising 0.560 g (0.208 mmol) of [ReO4] [NH4], 0. 118 g (0.622 mmol) of SnCl2. 2H2O and 5.0 g (27.1 mmol) of citric acid in dichloromethane (10 ml). After stirring for 2 hours at ambient

temperature, the solvent is evaporated and the residue, taken up in dichloromethane, is chromatographed on a column of silica gel (eluent: petroleum ether/dichloromethane: 60/40) and then recrystallized from a petroleum ether/dichloromethane mixture.

0.090 g of complex is thus obtained in the form of green crystals (yield = 61%).

The characteristics of this complex are as follows: - M = 709. 90 ; - M.p. = 205-207°C ; - Rf = 0.50 (petroleum ether/CH2Cl2 : 80/20); H NMR (CDCl3) : 7. 29 (m, J = 3.5 Hz, 5H, H4, Hs and H10), 7.44 (t, J = 8.0 Hz, 4H, Hg), 7.63 (dd, J = 8.0 Hz and J = 2.5 Hz, 2H, H3), 7.96 (dd, J = 8. 5 Hz and J-1. 5 Hz, 4H, Hg).

13C NMR (CDCl3) : 123. 7 (C3), 126.4 (C4), 127.2 (C8), 130.8 (Cg), 132.1 (C5), 132.3 (C10), 133.9 (C7), 141.7 (C2), 232. 8 (CS2 6), 237. 6 (CS2 1).

Mass spectrometry (FAB): m/z = 709. 8527: [M+#] ; 556.9 : [M- (PhCS2)]+; 493.0 : [Re (PhCS2) 2]- Elemental analysis: empirical formula: C21H15S8Re.

Experimental: % C = 35. 34 % H = 2.13 % S = 35.99 Calculated: % C = 35.35 % H = 2.13 % S = 36.03 Infrared (KBr disc): 1 482 (m), 1 442 (s), 1 332 (m), 1 311 (w), 1 263 (s), 1 234 (w), 1 179 (w), 1 156 (w), 1 096 (m), 1 028 (m), 997 (s, Vc-s), 947 (w), 908 (w), 802 (m), 755 (s), 681 (w), 652 (w), 544 (s, vS-S), 454 (m), 399 (m, VRe-s).

b) Preparation of the final complex 0.032 g (1.41 mmol) of sodium diethyldithiocarbamate, in the minimum amount of methanol (10 ml), is added dropwise to a solution of 0.020 g (0.028 mmol) of [Re (S3CPh) 2 (S2CPh)] in dichloromethane (10 ml). After stirring for 1 hour at ambient temperature, the solvent is evaporated and the residue, taken up in dichloromethane, is chromatographed on a column of silica gel (eluent: petroleum ether/dichloromethane : 70/30) and then recrystallized from a petroleum ether/dichloromethane mixture.

0.020 g of complex is thus obtained in the form of khaki green crystals, which corresponds to a quantitative yield.

The characteristics of the complex are identical to those in Example 1.

Example 8: Preparation of bis (trithioperoxybenzoato)- (dimethyldithiocarbamato) rhenium (III) [Re (PhCS3) 2 (Me2NCS2) In this example, the same procedure as in Example 7 is followed, using sodium dimethyldithiocarbamate instead of sodium diethyldithiocarbamate.

0.015 g of complex is thus obtained in the form of green crystals, which corresponds to a yield of 79%.

The characteristics of the complex are identical to those in Example 2.

Example 9: Preparation of bis (trithioperoxybenzoato)- (N-piperidyldithiocarbamato) rhenium (III) [Re (PhCS3) 2 (C5HloNcs2 ?] In this example, the same procedure as in Example 7 is followed for preparing the complex of Example 3, using piperidyldithiocarbamate instead of diethyldithio- carbamate.

0.015 g of complex is thus obtained in the form of green crystals, which corresponds to a yield of 75%.

The characteristics of the complex are identical to those in Example 3.

Example 10: Preparation of bis (trithioperoxybenzoato)- (diethyldithiocarbamato) technetium (III) [Tc (PhCS3) 2 (Et2NCS2)] In this example, the second embodiment of the process of the invention is followed for preparing the technetium complex. a) Preparation of the complex [Tc (PhCS3)2(PhCS2)] 0.4 to 0.8 GBq of sodium pertechnetate NaTcO4 is added to a flask comprising 75.0 mg of calcium gluconate, 0.75 mg of SnCl2-2H2O and 25.0 mg of sodium chloride dissolved in 10 ml of physiological saline. The mixture is stirred at ambient temperature for 10 minutes, then 20 mg of sodium dithiobenzoate NaPhCS2, dissolved in 1.0 ml of physiological saline under warm conditions, are added and the solution is heated at 100°C for an additional 15 minutes.

The complex obtained has the following characteristics: - Rf = 0.62 (petroleum ether/CH2Cl2 : 70/30). b) Preparation of the final complex 0.098 g (0.410 mmol) of sodium diethyldithiocarbamate in the minimum amount of methanol (10 ml) is added dropwise to a solution of 0.051 g (0.082 mmol) of [Tc (S3CPh) 2 (S2CPh)] in dichloromethane (10 ml). After stirring for 1 hour at ambient temperature, the precipitate is filtered off, washed several times with methanol, chromatographed on a column of silica gel (eluent: petroleum ether/dichloromethane: 70/30) and then recrystallized from a petroleum ether/ dichloromethane mixture.

0.033 g of complex is thus obtained in the form of pink crystals, which corresponds to a yield of. 66%.

The characteristics of the complex are as follows: - M = 616. 85; - Rf = 0. 50 (petroleum ether/CH2Cl2 : 70/30); 1H NMR (CDC13) : 1.17 (t, 6H, CH3), 3.66 (m, 4H, CH2), 7.46 (m, 6H, H8 + H6), 8.10 (m, 4H, H7).

3C NMR (CDC13) : 12.6 (CH3), 44.5 (CH2), 128.6 and 129.5 (C6 and 7), 132.2 (C8), 138.2 (C5), 200.0 (NCS2), 225.7 (CS3).

Infrared (KBr disc): 2 952 (m), 2 915 (m), 2 854 (m), 1 504 (s), 1 499 (m), 1 458 (m), 1 440 (m), 1 376 (w), 1 274 (m), 1 207 (m), 1 180 (w), 1 148 (m), 1 074 (w), 1 001 (m), 999 (s, Vc=s), 904 (s), 756 (s), 731 (m), 683 (s).

Example 11: Preparation of bis (trithioperoxybenzoato)- ([4-(2-methoxyphenyl) piperazin-1-ylethyl] dithio- carbamato) technetium (III) In this example, the same procedure as in Example 10 is followed for preparing this technetium complex, using, instead of sodium diethyldithiocarbamate, the dithiocarbamate of formula (VII): A biological molecule, 1-(2-methoxyphenyl) piperazine, which has a high affinity for some receptors located on the neurotransmitters, is thus introduced into the complex.

The dithiocarbamate of formula (VII) is prepared in the following way.

The starting material is 2-bromoethylamine and the final salt is obtained in four stages: - protection of the primary amine; - introduction of the 1- (2-methoxyphenyl) piperazine ; - deprotection of the amine; and - formation of the dithiocarbamate functional group. a) Protection of 2-bromoethylammonium bromide This reaction corresponds to the following scheme:

14 mmol (2.87 g) of 2-bromoethylammonium bromide 1 and 14 mmol (1.95 ml, 1.42 g) of triethylamine are dissolved with stirring in 100 ml of dichloromethane in a 150 ml two-necked flask. 10 mmol (1.51 g) of para- nitrobenzaldehyde 2 are added to the solution and the mixture is kept stirred overnight.

The solvent is evaporated and the resulting yellow solid is taken up in 50 ml of dichloromethane and 50 ml of water. The organic phase is extracted with 3 X 25 ml of dichloromethane and washed with 3 X 25 ml of water, then dried over magnesium sulphate and concentrated under vacuum. 2.16 g of yellow solid 3 are obtained.

The yield is 80%.

The characteristics of the product 3 are as follows: 1H NMR (CDC13) 8 in ppm: 3.74 (t, 2H, H7, J6-7 = 6.0 Hz), 4.10 (td; 2H, H6, J5-6 = 1.2 Hz), 7.94 (m, 2H, H3), 8.29 (m, 2H, H2, J2-3 = 8.8 Hz), 8.39 (m, 1H, H5, J5-6 = 1. 2 Hz).

13C NMR (CDC13) 8 in ppm: 32. 0 (C7), 62.1 (C6), 123.5 and 128. 9 (C2 and C3), 140. 8 and 148. 9 (Ci and C4), 160. 6 (Cs).

Infrared spectrum (v in cm~1) : 3 100-3 075 (w, aromatic CH), 2 882-2 827 (w, aliphatic CH), 1 645 (m, C=N), 1 603 (m, C=C), 1 523 (s, NO2), 1 424 (w, CH2), 1 342 (s, NO2), 1 266 (m, C-N), 567 (w, C-Br). b) Introduction of the 1-(2-methoxyphenyl) piperazine This reaction corresponds to the following scheme: 12.02 mmol (2.31 g) of 1-(2-methoxyphenyl) piperazine 4 and 12.02 mmol (1.21 g, 1.68 ml) of triethylamine are dissolved in 100 ml of dichloromethane in a 100 ml round-bottomed flask. 8.02 mmol (2.06 g) of the Schiff base 3 are added to the solution with stirring. The mixture is kept stirred at ambient temperature overnight.

The solvent is evaporated and the yellow residue obtained is taken up in 50 ml of dichloromethane and 50 ml of water. The organic phase is extracted with 3 x 20 ml of dichloromethane and washed with 3 X 20 ml of water, then dried over magnesium sulphate and concentrated under vacuum. The residue obtained is dissolved in 30 ml of ether and the resulting pale yellow solid 5 (1.79 g) is filtered off and washed with

ether. The yield is 60%.

The characteristics of the product 5 are as follows: 1H NMR (CDCl3) $ in ppm: 2.81 (m, 6H, H7 and H8), 3.12 (m, 4H, Hg), 3.88 (s, 3H, Hie), 3.89 (m, 2H, H6), 6.94 (m, 4H, aromatic H), 7. 91 (m, 2H, H3, J2-3 = 8. 8 Hz), 8.28 (m, 2H, H2), 8.41 (m, 1H, H5). <BR> <BR> <P>13C C NMR (CDCl3) # in ppm: 50.2 and 53.4 (C8 and Cg), 55.0 (C16), 58.3 and 59.0 (C6 and C7), 110.8, 117.8, 120.6 and 122. 6 (Cll to C14), 123. 5 and 128. 4 (C2 and C3), 140.9 and 148.7 (C1 and C4), 141.3 and 151.9 (C10 and C15), 159.2 (C5).

Infrared spectrum (v in cm-1) : compound 5: 2 944 (m, CH3), 2 811 (m, CH2), 1 648 (m, C=N), 1 601 (m, C=C), 1 522 (s, NO2), 1 458 (m, CH2, CH3), 1 342 (s, NO2), 1 239 (m, C-O). c) Deprotection of the amine according to the following reaction scheme

4.34 mmol (1.60 g) of the product 5 are dissolved in 30 ml of dichloromethane in a 100 ml round-bottomed flask. 13 ml of a molar hydrochloric acid solution are added with stirring to the solution. Stirring is then maintained for 2 hours at ambient temperature. The aqueous phase is extracted with 3 x 10 ml of water and neutralized with 13 ml of a molar sodium hydroxide solution. The organic phase is taken up in 3 X 10 ml of dichloromethane, then washed with 3 x 5 ml of water, dried over magnesium sulphate and concentrated under vacuum. After evaporating the solvent, 0.53 g of a yellow oil 7 are obtained, which corresponds to a yield of 51%.

The characteristics of the product 7 are as follows: 'H NMR (CDC13) 8 in ppm: 2.51 (t, 2H, H2, J1-2 = 6.1 Hz), 2.67 (m, 4H, H3), 2.85 (t, 2H, H1, Jl-2 = 6. 1 Hz), 3.10 (m, 4H, H4), 3.86 (m, 3H, Han), 6.93 (m, 4H, aromatic

H).

"C NMR (CDC13) 8 in ppm: 38.2 (C1), 50.3 and 53. 1 (C3 and C4), 55. 0 (C1l), 60.6 (C2), 110.8, 117.8, 120.6 and 122.5 (C6 to Cg), 141.0 and 152.0 (C5 and Ciao). d) Formation of the dithiocarbamate functional group according to the following reaction scheme 2.25 mmol (0.53 g) of the amine 7 are dissolved in 2 ml of water in a 100 ml two-necked flask. 10 ml of an aqueous sodium hydroxide solution (2.60 mmol) are added to the solution, followed by 12 ml of acetone, and the resulting mixture is stirred until a clear solution is obtained. 2.80 mmol (0.21 g, 0.17 ml) of carbon disulphide 8 are added dropwise and with stirring to the mixture. The solution is cooled using an ice bath and maintained at low temperature (with an ice bath) for 5 hours and with stirring, and then the mixture is placed at 0°C overnight. The solvent is subsequently evaporated and the residue obtained is washed with ether. 0.48 g of product 8 is obtained, i. e. a yield of 64%.

The characteristics of the thiocarbamate 8 are as follows: 1H NMR (CDC13) 8 in ppm: 2.63 (m, 6H, H2 and H3), 2.98 (s, 4H, H4), 3.67 (t, 2H, H1, Jl-2 = 6. 8 Hz), 3.76 (s, 3H, Han), 7.01 (m, 4H, aromatic H).

3C NMR (CDC13) 8 in ppm: 50.2 and 52.8 (C3 and C4), 55. 0 (C1l), 56.2 (C2), 110.8, 117.8, 120.6 and 122.8 (C6 to 9), 151.9 (C5-C10).

Infrared spectrum (v in cm-1) : 3 392 (NH), 2 939 (w, CH3), 2 829 (w, CH2), 1 498 (s, NH), 1 458 (m, C=C), 1 377 (w, CH2, CH3), 1 234 (s, C-O), 1 115 (m, C=S).

Sodium 2- [4- (2-methoxyphenyl) piperazin-1-yl] ethyl- dithiocarbamate is obtained with a good yield.

Example 12: Preparation of a dithiocarbamate comprising biotin Biotin is a vitamin present at a low concentration in the blood which can be used to diagnose or treat certain tumours (in particular, tumours of the abdomen). The method used can consist in injecting, into the body, an antibody to which has been attached a molecule specific for a substrate, in this instance avidin, which has a high affinity for biotin. These antibodies become located at the tumour. The biotin- comprising technetium complex is then injected into the body and will become located preferentially on the antibodies introduced above, which makes possible visualization of the tumour.

The dithiocarbamate used for the preparation of the complex corresponds to the following formula:

The starting material is the primary amine 1- (2-aminoethyl) piperazine and stages analogous to those described in Example 11 are carried out. a) Protection of the primary amine 14 mmol (1.81 g, 1.84 ml) of 1- (2-aminoethyl) piperazine are dissolved in 100 ml of dichloromethane with stirring in a 150 ml two-necked flask. 10 mmol (1. 51 g) of para-nitrobenzaldehyde are added to the solution and the mixture is kept stirred overnight at ambient temperature. The solvent is evaporated and the orange solid obtained is taken up in 50 ml of dichloromethane and 50 ml of water. The organic phase is extracted with 3 x 25 ml of dichloromethane and then washed with 3 X 25 ml of water, dried over magnesium sulphate and concentrated under vacuum. An orange solid is recovered (2.00 g, i. e. a yield of 76%).

The characteristics of this product are as follows: 1H NMR (CDC13) 8 in ppm: 2.55 (m, 4H, H2), 2.72 (m, 2H, H3, J3-4 = 7.0 Hz), 2.91 (m, 4H, Hl, Jl-2 = 4.8 Hz), 3.84

(m, 2H, H4), 7.89 (m, 2H, H7), 8.27 (m, 2H, H8), 8.38 (m, 1H, H5, J45 = 1. 3 Hz).

3C NMR (CDC13) 8 in ppm: 45.7 and 54.4 (C1 and C2), 59.1 (C4), 123. 5 and 128. 4 (C7 and C8), 141.3 and 148. 6 (C6 and Cg), 159. 2 (C5). b) Formation of the sodium dithiocarbamate salt 7.63 mmol (2.0 g) of the product obtained in a) are dissolved in 100 ml of dichloromethane in a 150 ml two- necked flask. 12 mmol (0.48 g) of sodium hydroxide are added to the solution with stirring. The mixture is cooled to-15°C using a bath of liquid nitrogen and 11 mmol (0. 84 g, 0.66 ml) of carbon disulphide are added dropwise to the solution with stirring. After returning to ambient temperature, the mixture is stirred overnight. The precipitate obtained is washed with 50 ml of dichloromethane and then 50 ml of ether and filtered off. It is dissolved in 100 ml of a dichloromethane/water (1: 1) mixture and the aqueous phase is extracted and concentrated under vacuum. A brown solid is obtained. c) Deprotection of the amine The solid obtained at the end of stage b) is dissolved in 50 ml of dichloromethane and 20 ml of water. 8 mmol (0.32 g) of sodium hydroxide are added to the solution and stirring is maintained for one hour. The aqueous phase is extracted with 20 ml of water and concentrated under vacuum. A brown solid is obtained (1.57 g, yield = 69%).

It corresponds to the formula:

1H NMR (D2O) 8 in ppm: 2.41 (m, 2H, H3), 2.49 (t, 4H, H2, J1-2 = 5. 2 Hz), 2.69 (m, 2H, H4), 4.26 (t, 4H, H1, Jl-2 = 5.1 Hz).

13C NMR (D2O) 8 in ppm : 36.9 (C4), 49.9 and 51.6 (C1 and C2), 58.8 (C3), 208.1 (C=S). d) Coupling of the biotin according to the following reaction scheme

The biotin is first of all esterified with N-hydroxysuccinimide and then reacted with the thiocarbamate obtained in stage c) in dimethylformamide (DMF). The biotin-comprising dithiocarbamate thus obtained is insoluble in this solvent and can be recovered.

Example 13: Preparation of the pyrrolidyldithio- carbamate In this example, the same procedure as in Example 3 is followed for preparing this dithiocarbamate, using: - 0. 025 mol (1.78 g, 2 ml) of pyrrolidine instead of the piperidine; - 0. 030 mol of NaOH (1.20 g); and - 0. 026 mol (1.98 g, 1.6 ml) of CS2- 1.94 g of a mixture comprising 37% of sodium pyrrolidyldithiocarbamate and 63% of pyrrolidinium pyrrolidyldithiocarbamate are thus obtained, which mixture has the following characteristics: 1H NMR: 1.90 (m, 6.8H, H2 and H4), 3.18 (m, 2.6H, H3, J3-4 = 7.3 Hz), 3.68 (m, 4.2H, Hl, J1-2 = 7.0 Hz).

3C NMR: 23. 3 (C4), 25.2 (C2), 45.2 (C3), 54.6 (C1), 202.2 (C=S).

Infrared spectrum (v in cm-1) : 2 943 (m, CH2), 2 868 (m, CH2), 1 420 (s, C-N), 1 400 (m, CH2), 1 160 (m, C=S).

Example 14: Preparation of sodium 1-ethylpiperazinyl- dithiocarbamate In this example, the same procedure as in Example 3 is followed for preparing this dithiocarbamate, using: - 0. 025 mol (2.85 g, 3 ml) of 1-ethylpiperazine instead of the piperidine; - 0. 030 mol (1.20 g) of NaOH ; and - 0. 026 mol (1.98 g, 1.6 ml) of CS2.

3.11 g of sodium 1-ethylpiperazinyldithiocarbamate are thus obtained, which product exhibits the following characteristics:

1H NMR: 1.01 (t, 3H, H4), 2.44 (q, 2H, H3, J3-4 = 7.3 Hz), 2.52 (m, 4H, H2), 4. 28 (m, 4H, Hui).

3C NMR : 10.0 (C4), 50.8 (C3), 49.8 and 59.9 (C1 and C2), 202.1 (C=S).

Infrared spectrum (v in cm-1) : 2 969 (w, CH3), 2 818 (m, CH2), 1 415 (s, C-N), 1 227 (s, C=S).

REFERENCES CITED [1] FR-A-2 698 272 <BR> <BR> <BR> <BR> <BR> <BR> [2] F. Mevellec et al., Inorg. Chem. Comm. , 2, 1999, 230-233 [3] Wei et al. , J. Am. Chem. Soc., 1990,112, 6433-6434 [4] McConnachie and Stiefel, Inorg. Chem., 1997, 36, 6144-6145 [5] McConnachie and Stiefel, Inorg. Chem. , 1999,38, 964-972